NM_002691.4:c.2716_2717del

POLD1 · NP_002682.2:p.(Arg906AspfsTer47) · NM_002691.4

GRCh37: chr19:50918842 CGA>C · GRCh38: chr19:50415585 CGA>C

Gene: POLD1 Transcript: NM_002691.4

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

POLD1

Transcript

NM_002691.4

Protein

NP_002682.2:p.(Arg906AspfsTer47)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002691.4:c.2716_2717del (p.Arg906AspfsTer47) is a frameshift null variant in POLD1, a gene in which loss of function is an established mechanism for polymerase proofreading-associated polyposis and cancer predisposition.

Under the ClinGen SVI PVS1 decision framework (PMC6185798), this frameshift deletion meets PVS1 at very strong strength: it is predicted to undergo nonsense-mediated decay (PTC in exon 23 of 27), affects the MANE Select transcript, and is absent from population databases.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles), meeting PM2 at moderate strength under non-VCEP population frequency thresholds (AF < 0.1%).

This variant is absent from ClinVar with no prior classifications or submissions. No variant-specific functional studies, case-control data, segregation data, or de novo reports were identified in the literature.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one very strong criterion (PVS1) plus one moderate criterion (PM2) yields a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	NM_002691.4:c.2716_2717del is a frameshift deletion in exon 21 of 27, predicted to cause a premature termination codon (p.Arg906AspfsTer47) in exon 23 that triggers nonsense-mediated decay. POLD1 loss of function is an established germline disease mechanism for polymerase proofreading-associated polyposis (PPAP) and cancer predisposition. Under the ClinGen SVI PVS1 framework (PMC6185798), this null variant meets PVS1 at full strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4
PS1	N/A	PS1 requires the same amino acid change as a previously established pathogenic variant. This is a frameshift deletion, not a single amino acid substitution; PS1 semantics do not apply.
PS2	Not met	No de novo data are available. No patient-level information or trio sequencing results are present in the case materials.
PS3	Not met	No variant-specific functional studies were identified. The literature pass returned zero PMIDs; OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. No systematically characterized range encompassing codon 906 was found. The PVS1 gene-context papers discuss POLD1 at the gene level only and do not report experimental data for this variant.	oncokb
PS4	Not met	No case-control or statistical enrichment data are available. The variant is absent from ClinVar and has no reported observations in affected individuals.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. The closest analog (PP5) would require a reputable source reporting the variant as pathogenic with unavailable independent evidence. No such source exists for this variant.
PM1	Not met	Although the variant truncates the C-terminal domain of POLD1, no domain-level functional characterization is available in the case materials to support PM1 application. The variant is absent from cancerhotspots.org and no paper in the case literature characterizes codon 906 or the surrounding region as a critical functional domain. Domain-level inference alone without a citable source is insufficient for PM1.
PM2	Met	NM_002691.4:c.2716_2717del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under non-VCEP gnomAD cutoffs, an allele frequency below 0.1% in all population databases supports PM2 at moderate strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is an out-of-frame (frameshift) deletion producing a premature termination codon. The null effect is already captured by PVS1; applying PM4 would double-count the same molecular consequence.
PM5	N/A	PM5 requires a novel missense change at the same amino acid residue as a known pathogenic missense variant. This is a frameshift deletion, not a missense change. The PM5 candidate harvest confirmed no classic same-residue missense comparator semantics apply.	pm5_candidates
PM6	Not met	PM6 applies to assumed de novo events without confirmation of paternity and maternity. No de novo data are available for this variant.
PP1	Not met	No segregation data are available. No family studies or co-segregation analyses were identified for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a frameshift deletion, not a missense variant.
PP3	Not met	PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to indels. HCI prior is not available for POLD1. No in silico evidence beyond what PVS1 captures from the variant type itself is present. PP3 should not be stacked on top of PVS1 for the same null-effect prediction.	spliceai
PP4	Not met	No patient phenotype or family history data are available in the case materials to assess whether the clinical presentation is highly specific for POLD1-related disease.
PP5	Not met	No reputable source has reported NM_002691.4:c.2716_2717del as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.00, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0.00, below the 0.3% BS1 threshold for a disorder with high penetrance.	gnomad_v2 gnomad_v4
BS2	Not met	No observations of this variant in healthy adults are documented. The variant is absent from all population databases, precluding BS2 application.
BS3	Not met	No functional studies demonstrating a benign effect are available. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. No literature was identified for this variant.	oncokb
BS4	Not met	No segregation data are available to demonstrate lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating (frameshift) variant in a gene where loss of function is the established disease mechanism.
BP2	N/A	BP2 applies to variants observed in trans with a pathogenic variant for a fully penetrant dominant disorder. No such data are available and POLD1-related disease is autosomal dominant; observing a second pathogenic allele in trans would not be expected.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is an out-of-frame (frameshift) deletion.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene product. SpliceAI shows no splice alteration (max delta = 0.00), but this alone does not constitute multiple lines of benign evidence. For a frameshift null variant, in silico predictors are not the appropriate tool to assess impact; the variant type itself is inherently damaging.	spliceai
BP5	Not met	BP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such data are available for this variant.
BP6	Not met	No reputable source has reported NM_002691.4:c.2716_2717del as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a frameshift deletion with a profoundly altered protein product.
PM3	N/A	PM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). POLD1-related cancer predisposition is autosomal dominant; PM3 is not applicable.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.